Research

PPI-type Receptors of plant hormones and the natural product chemical biology that regulates them: Plant hormones are biologically active natural products that regulate most physiological functions in plants. Individual plants have from a dozen to more than 100 different receptor subtypes for a single plant hormone (genetic redundancy), which allows plant hormones to regulate diverse biological responses. The plant hormone (3R, 7S)-jasmonoyl-L-isoleucine (JA-Ile) acts as a molecular glue, inducing a protein-protein interaction (PPI) between two proteins, COI1 and JAZ. In the model plant Arabidopsis thaliana, one COI1 protein and 13 JAZ proteins (JAZ1-13) are present, and their combination gives rise to 13 PPI-type COI1-JAZ co-receptor subtypes. Each co-receptor subtype is responsible for the regulation of many interesting biological responses, such as defense against foreign enemies (pests, pathogen infection) and production of secondary metabolites (medicinal resource natural products, etc.). On the other hand, some COI1-JAZ co-receptor subtypes are responsible for a troublesome “side effect” of plant growth inhibition. Our research objective is to develop molecular technologies to freely control the biological activity of plant hormones with numerous receptors, such as the development of molecular glues that freely control protein-protein interactions (PPIs) by chemical biology using natural products as tools. So far, we have constructed a library of stereoisomers of natural product coronatines and from screening with them, we have selectively bound to COI1-JAZ9&10 and COI1-JAZ9 co-receptor subtypes. We developed agonists that selectively bind to the COI1-JAZ9 co-receptor subtype. These have also been used to elucidate and regulate signaling induced by a single subtype for the first time ever. The development of “molecular targeted functional modification,” which improves plant functions and confers superior traits by controlling the activity of plant hormones based on their mechanism of action, is expected to be promoted. By realizing “molecular targeted functional modification,” which improves plant functions by inducing only what is desired from among the diverse biological activities of JA-Ile, we can realize “pesticide-free food production through enhanced defense against foreign enemies” and “green chemistry for the production of valuable plant metabolites through enhanced secondary metabolism.

The mechanism of action for JA-Ile. The way in which JA-Ile binds to receptors and induces biological responses is shown in Figure 2. JA-Ile functions as a “natural PROTAC molecule” and induces a protein-protein interaction between the F-Box protein COI1 and the transcriptional repressor JAZ (binding to the COI1-JAZ co-receptor, Fig. 1 & 2). This leads to polyubiquitination of JAZ and its degradation by the 26S proteasome pathway. By inducing JAZ degradation, JA-Ile activates more than 25 transcription factors, which are repressed by 13 different JAZs (Fig. 2), resulting in a variety of biological responses happening simultaneously. The COI1-JAZ co-receptor agonist is a potent activator of a wide range of biological responses (Fig. 2) and has been used to selectively bind to a single co-receptor subtype to activate only beneficial responses.

Natural Products Chemical Biology of Molecular Evolution of Plant Hormones and Receptors: The acquisition of defense responses against new foreign enemies, such as pathogens and herbivores, was essential when plants transitioned from aquatic to terrestrial environments during their evolution. In response, a signal transduction system including a primitive plant hormone and its receptor, which is the ancestor of the plant hormone JA-Ile that is responsible for plant defense responses, is thought to have arisen (Fig. 3).

Marchantia polymorpha, considered to be the ancestor of land plants, has been the subject of active research on the origin of plant hormones. In an international collaborative study, we discovered a primordial hormone made from C20-long-chain unsaturated fatty acids (C20 = 20 carbons) (Fig. 3). In animals, an autacoid hormones called prostaglandins made from C20-long-chain unsaturated fatty acids are well known. However, plant hormones responsible for defense responses in higher plants are made from C18- or C16-long-chain unsaturated fatty acids, and it was thought that no hormones derived from C20-long-chain unsaturated fatty acids existed in plants. This is an epoch-making achievement that proves the existence of hormones derived from C20-long-chain unsaturated fatty acids in plants as well as in animals. We are currently studying the molecular evolution of phytohormone receptor systems and the regulation of signal transduction using the primordial hormone system of Marchantia polymorpha.